Dataset Information

Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina.

ABSTRACT: Pericyte loss and deficient vascular platelet-derived growth factor receptor-? (PDGFR?) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid ?-protein (A?) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant A? deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFR? in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFR? loss significantly associated with increased retinal vascular A?40 and A?42 burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFR? and A?40 levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral A? burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFR? loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.

SUBMITTER: Shi H

PROVIDER: S-EPMC7181564 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina.

Shi Haoshen H Koronyo Yosef Y Rentsendorj Altan A Regis Giovanna C GC Sheyn Julia J Fuchs Dieu-Trang DT Kramerov Andrei A AA Ljubimov Alexander V AV Dumitrascu Oana M OM Rodriguez Anthony R AR Barron Ernesto E Hinton David R DR Black Keith L KL Miller Carol A CA Mirzaei Nazanin N Koronyo-Hamaoui Maya M

Acta neuropathologica 20200210 5

Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid β-protein (Aβ) d ...[more]

PMID: 32043162

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Project description:Reduced cerebral blood flow impairs cognitive function and ultimately causes irreparable damage to brain tissue. The gliovascular unit, composed of neural and vascular cells, assures sufficient blood supply to active brain regions. Astrocytes, vascular smooth muscle cells, and pericytes are important players within the gliovascular unit modulating vessel diameters. While the importance of the gliovascular unit and the signals involved in regulating local blood flow to match neuronal activity is now well recognized, surprisingly little is known about this interface in disease. Alzheimer's disease is associated with reduced cerebral blood flow. Here, we studied how the gliovascular unit is affected in a mouse model of Alzheimer's disease, using a combination of ex vivo and in vivo imaging approaches. We specifically labelled vascular amyloid in living mice using the dye methoxy-XO4. We elicited vessel responses ex vivo using either pharmacological stimuli or cell-specific calcium uncaging in vascular smooth muscle cells or astrocytes. Multi-photon in vivo imaging through a cranial window allowed us to complement our ex vivo data in the presence of blood flow after label-free optical activation of vascular smooth muscle cells in the intact brain. We found that vascular amyloid deposits separated astrocyte end-feet from the endothelial vessel wall. High-resolution 3D images demonstrated that vascular amyloid developed in ring-like structures around the vessel circumference, essentially forming a rigid cast. Where vascular amyloid was present, stimulation of astrocytes or vascular smooth muscle cells via ex vivo Ca(2+) uncaging or in vivo optical activation produced only poor vascular responses. Strikingly, vessel segments that were unaffected by vascular amyloid responded to the same extent as vessels from age-matched control animals. We conclude that while astrocytes can still release vasoactive substances, vascular amyloid deposits render blood vessels rigid and reduce the dynamic range of affected vessel segments. These results demonstrate a mechanism that could account in part for the reduction in cerebral blood flow in patients with Alzheimer's disease.media-1vid110.1093/brain/awv327_video_abstractawv327_video_abstract.

Dataset Information

Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina.

Publications

Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina.

Similar Datasets

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